In this revised application, we propose a novel approach to understanding the pathophysiology of Attention- Deficit/Hyperactivity Disorder (ADHD) by linking a neural circuit that has been associated with slower and more variable responses to increased intra-subject response time variability in children with ADHD. Based on extensive preliminary data in adults and children with ADHD, we hypothesize that ADHD-related abnormalities in functional connectivity (regional temporal coherence) in a circuit linking the right dorsal anterior cingulate cortex (dACC) to the retrosplenial complex (RSC; comprising precuneus and posterior cingulate cortex) which is involved in high level integration between posterior association processes and anterior executive functions, plays a key pathophysiological role in ADHD. We propose to characterize this novel locus of dysfunction by scanning 100 right-handed children so that we can analyze full imaging and neuropsychological data from at least 37 children with combined-type ADHD and 37 age-, IQ- socioeconomic status, handedness- and sex- matched healthy comparisons. We will (1) use fMRI to confirm our preliminary findings of weaker dACC/RSC functional connectivity associated with ADHD; and (2) determine whether ADHD-related increases in trial-by- trial response time variability are related to differences in the functional integrity of the dACC/RSC circuit. We will also conduct diffusion tensor imaging (DTI) studies to examine the relationship between functional and structural integrity of this key circuit, and explore key neuropsychological measures in relation to our cutting- edge measures of functional connectivity. This proposal, which combines novel methods and hypotheses with substantial preliminary data, has the potential to delineate brain-behavior relationships that will inform translational models of pathophysiology of this common and highly impairing disorder. PUBLIC HEALTH RELEVANCE: We propose to apply novel neuroimaging methods to better understand the brain mechanisms involved in Attention-Deficit/Hyperactivity Disorder (ADHD) in children. Individuals with ADHD are consistently inconsistent in their responses, and we will study a brain circuit that is associated with such inconsistency in a total of 100 children, about half of whom have ADHD and about half of whom are healthy subjects. The proposed study will allow us test a new theory about a the dysfunction of a specific brain circuit in ADHD which is believed to connect and coordinate key front and back parts of the brain. Achieving such a level of detailed information about brain functioning in ADHD would have major impact on our ability to improve methods of diagnosing ADHD and of developing new treatments. [unreadable] [unreadable] [unreadable]